Several polypeptide growth factors have been identified with the ability to induce blood vessel development (angiogenesis), and the overall project goal is to utilize such growth factors to facilitate coronary collateral development in patients with ischemic heart disease. We have shown that basic fibroblast growth factor (bFGF) and vascular endothelial growth factor, both angiogenic polypeptide growth factors, enhance coronary collateral development in dogs when administered repeatedly into the coronary circulation, or, in the case of bFGF, when administered daily into the systemic arterial circulation for seven days. These routes of administration, although acceptable in experimental animals, are not practical in human subjects. Most recently, we have shown that two single doses of bFGF administered into the left main coronary artery enhance coronary collateral flow in dogs, a regimen that would be feasible in human subjects. Dogs were subjected to gradual occlusion of the left circumflex coronary artery and randomized to receive bFGF 100 micrograms/kg or a vehicle control as an intracoronary bolus on one or two occasions (2 days between doses). Collateral perfusion was assessed during maximal coronary vasodilatation 17 days after treatment. Maximal collateral flow in dogs that received two doses of bFGF exceeded that of control dogs by 39% (P<0.0005). Based on these and a number of earlier investigations, we have obtained an IND (Investigational New Drug) for a Phase I study in human subjects. This is a randomized, double-blind safety study with a typical dose escalation format in which bFGF (or vehicle) is administered into the coronary circulation. The first patients entered into the study in July, 1995. Additional preclinical studies are underway to assess the potential of gene therapy to effect coronary angiogenesis. Gene therapy represents an attractive alternative to the administration of polypeptide growth factors. Sustained local expression of angiogenic gene products could result in site-specific angiogenic stimulation following a single intracoronary treatment.